Medical Device Link.

REGULATIONS AND STANDARDS

Time to prepare

On 5 September 2007, Medical Device Directive (MDD) 2007/47/EC was published, which amends and clarifies the earlier medical device Directives 93/42/EEC and 90/385/EEC.¹ It will have a major affect, particularly on manufacturers of implantable and Class III devices, because Notified Bodies will focus more on clinical data and will more often require clinical investigations in the course of the conformity assessment of innovative medical devices. The new regulation will come into force on 21 March 2010. In the meantime, medical device manufacturers will be expected to familiarise themselves with the extended requirements and take appropriate measures to comply with them.

This article provides an overview of the regulations for the clinical evaluation of medical devices using both the “literature route” and the “clinical investigation route.” It will also discuss the relevant MEDDEV guidance documents.

Clinical evaluation of medical devices

According to Clause 1.1, Annex X of the amending MDD 2007/47/EC, medical device manufacturers in Europe must provide a formal document, referred to as a Clinical Evaluation, irrespective of the classification of the medical device in question. The clinical evaluation document will become an obligatory document that must be provided by the medical device manufacturer in the course of his conformity assessment. Therefore, clinical evaluation has to be part of the technical documentation for the respective device (Clause 1.1b.) and must be actively kept updated and consider the postmarketing results obtained after placing the product on the market (Clause 1.1.c). In addition, the amending MDD states that clinical investigations are, in particular, expected for implant devices and for Class III devices (Clause 1.1a, Annex X).

In Clauses 1.1 and 1.1a of Annex X it becomes clear that a manufacturer can use his own clinical data for the evaluation or he can make use of comparable medical devices. However, in the latter case, the manufacturer must actively document and justify the equivalence of the medical device to be evaluated with the predicate device he uses for comparison.

Typically, a product can be assumed to be equivalent if it has the same technological characteristics (geometry and surface properties), is made of comparable material, has the same chemical composition, is subjected to comparable manufacturing processes (including sterilisation process) and is used for the same purpose (intended use including nature and duration of body contact). From this list it becomes obvious that the documentation of equivalence may sometimes be difficult.

Clause 1.1.a of Annex X states that clinical investigations become a mandatory prerequisite for the clinical evaluation of implantable and Class III devices, and particular justification is required if a manufacturer uses existing clinical data, that is, clinical data that were obtained with a comparable medical device (predicate device). This requirement goes far beyond those of the former medical device Directives.

MEDDEV guidance for clinical evaluation

MEDDEV documents are European guidelines issued by the European Commission to help manufacturers and Notified Bodies comply with applicable Directives. With regard to the clinical evaluation of medical devices (literature route/clinical investigation route), the following MEDDEV documents have been issued:

• MEDDEV 2.7.1. Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies (April 2003)
• MEDDEV 2.12-2 Guideline on Postmarket Clinical Follow-Up (May 2004).

Two other guidelines are also available, issued by the European Notified Bodies Co-Ordination Medical Devices Group:

• NB-MED/2.7/Rec3 Evaluation of Clinical Data. Chapter 2.7. Clinical Investigations, Clinical Evaluation (revised 11.5.1999)
• NB-MED/2.7/Rec1 Guidance on Clinicals. Chapter 2.7. Guidance on when a clinical investigation is needed for CE marking (revised 20.4.1998).

Today, Notified Bodies expect medical device manufacturers to comply in particular with MEDDEV 2.7.1 for their clinical evaluations, because this document essentially contains the recommendations of the aforementioned NB-MED 2.7 guidelines. According to MEDDEV 2.7.1, which fully complies with the provisions of the amending MDD, a clinical evaluation can be based on clinical investigations actually performed by the manufacturer with the device in question and/or a systematic literature review. In both cases the guideline requests a prospective clinical evaluation plan, which should describe the procedure to be followed, which kind of clinical data are to be evaluated, and which questions are to be answered and documented in the clinical evaluation report.

Sources of data

Table I: The information that must be provided in the clinical evaluation report. (click image to enlarge)

With regard to clinical data to be evaluated, MEDDEV 2.7.1, accepts the following sources:

• Results from clinical investigations with the manufacturer’s investigational device
• Results from clinical investigations with CE-marked predicate devices
• Published data from clinical studies or other clinical results with comparable medical devices
• Postmarketing surveillance data with the device in question or with comparable devices.

If the manufacturer makes use of clinical data that were not obtained with the medical device in question, the level of comparability must be described and justified. With regard to postmarketing surveillance data, the report should specify an appropriate reporting period and should state the number of sold devices, the total number of complaints and the total number and nature of clinically relevant complaints/notified adverse reactions. Table I lists the information the authors must provide in the clinical evaluation report. Furthermore, the author(s) must declare to be unbiased in their assessment and scientifically qualified to perform the clinical evaluation. For this, an abbreviated CV of the author(s) should be attached to the clinical evaluation report. At the end of the clinical evaluation report, all search runs that were conducted, including the received search results, should be attached. With regard to the selected and evaluated literature, at least the abstracts or better, complete copies of the respective documents should be attached to the clinical evaluation report.

Clinical investigation of medical devices

If an initial clinical evaluation concludes that an innovative or substantially modified medical device cannot be fully evaluated regarding its clinical effectiveness and/or safety, the medical device manufacturer will need to perform a clinical investigation to generate appropriate clinical data. In unclear cases, the Notified Bodies’ recommendation NB-MED/2.7/Rec1 can give advice. According to this guideline, a clinical study should be performed

• where a completely new device is proposed for the market, whose components, features and/or method of action are previously unknown
• where an existing device is modified and the modification might significantly affect the clinical safety and performance
• where a previously established device is proposed for a new indication
• where a device incorporates new materials, previously unknown, coming into contact with the human body or existing materials applied in a location not previously exposed to that material, and for which there is no convincing prior experience, or that the device will be used for a significantly longer time.

If a clinical investigation is required, the amending MDD (and the former MDD and AIMDD) gives a brief list of requirements with which a sponsor (medical device manufacturer or other organisation initiating a clinical investigation) must comply. For the MDD, this is specified in Annex X of Article 15 and for the AIMDD, it is in Annex 7 of Article 10.

EN ISO 14155 Parts 1 and 2

Table II: The information that must be provided in the clinical evaluation report. (click image to enlarge)

EN ISO 14155² was developed under the former MDD and AIMDD to describe the procedures that need to be followed in a clinical investigation. This standard is intended “to be applied worldwide to clinical investigations of medical devices to fulfill the technical aspects of the various national, regional and international regulatory requirements.”

Because legal regulatory requirements differ throughout the world (to some extent even between European countries), regulatory specifications have been excluded from the scope of EN ISO 14155. Therefore, a clinical investigation must always comply with the applicable national law(s) and EN ISO 14155 Parts 1 and 2, which replaced EN 540:1993, Clinical Investigation of Medical Devices for Human Subjects. EN ISO 14155 does not apply to in vitro diagnostic medical devices. Any clinical study that meets the requirements of EN ISO 14155 Parts 1 and 2 will be regarded as fulfilling the requirements of the underlying MDD and AIMDD. The study results obtained in compliance with this standard will be accepted by any Notified Body or Competent Authority to contain scientifically sound and reliable results.

Core elements of EN ISO 14155 Part 1

Prerequisites. EN ISO 14155 Part 1, General Requirements, specifies general criteria intended to protect human subjects, to ensure the scientific conduct of the study and to assist sponsors, monitors, investigators, ethics committees, regulatory authorities and Notified Bodies involved in the conformity assessment of medical devices. It is interesting to see that clinical investigations of medical devices are fully embedded into the general risk management process of a medical device manufacturer. Therefore, Part 1 requires a critical review of published and available unpublished medical and scientific data and an evaluation of the potential clinical risks identified for the investigational device in the context of a risk management process according to EN ISO 14971.³ A clinical study can only be performed on this basis and after giving documented evidence of a positive risk versus benefits ratio. With regard to the critical literature review, Annex A of Part I provides practical instruction on how to conduct a scientifically valid and methodologically sound literature review. The recommendations given in this Annex are similar to the recommendations provided in MEDDEV 2.7.1.

Ethical considerations. According to Clause 5, the rights, safety and wellbeing of study subjects shall be protected consistent with the ethical principles laid down in the Declaration of Helsinki. EN ISO 14155 Part 1 reinforces the importance of ethical considerations in a clinical trial and Annex B gives a list of relevant information to be submitted to the ethics committee. Clause 6.7 provides detailed requirements regarding the information to be provided to the study subjects and how to obtain informed consent. The sponsor must document any compensation that is given to the investigators, study subjects, clinical monitors or any parties participating in or contributing to the clinical investigation to avoid improper influence or inducement. Finally, the sponsor must make provision for compensation of study subjects in the event of injury arising from participation in the clinical investigation. These general ethical provisions are, of course, regulated in more detail in the national medical device laws.

General requirements. There is a long list of general requirements that need to be complied with when conducting a clinical investigation, see Table II.

Personal responsibilities. Detailed assignments of responsibilities are specified for all parties involved in a clinical investigation. It is the responsibility of the sponsor to define, establish, allocate and communicate all study related duties, responsibilities and functions (Clauses 8, 9, 10).

Final Report. After completion of the clinical study, a final report has to be provided, irrespective of the study outcome and even when a study has been terminated prematurely. The final report is the responsibility of the sponsor and all participating investigators and all those contributing must sign the report. Annex C provides excellent guidance on how to write a final report and how to structure the document.

Core elements of EN ISO 14155 Part 2

EN ISO 14155 Part 2, Clinical Investigation Plan (CIP) is the most important document to be prepared to ensure a scientifically sound and administratively correct conduct of a clinical investigation. Because of its importance, this part of the standard provides detailed requirements for this document and introduces a normative and scientific approach to the preparation of a CIP, formerly known as the protocol or clinical protocol. Part 2 of EN ISO 14155 also addresses the justification for the study, its design and its population, including issues of study size and statistical considerations. Safety definitions for reporting purposes are substantiated. A CIP must, of course, contain all relevant information on the investigational device, the sponsor, involved clinical institutions, clinical investigators, monitoring arrangements, data and quality management and must be approved in writing by all involved parties. As outlined already, the CIP must summarise the current literature, justify the planned study design and disclose any preclinical investigations, previous clinical experience and possible risks associated with the use or administration of the investigational device. Most importantly, the CIP must justify the clinical endpoints and their success and failure criteria. Inclusion and exclusion criteria for the study population must be listed, the methods and timing for assessing, recording and analysing study variables must be described, and a (statistical) justification must be provided for the planned number of subjects to be included in the study.

Clause 4.8 of Part 2 includes clear requirements regarding the statistical grounds of a clinical investigation. Accordingly, the CIP must include a description and justification of hypotheses and statistical design, methods and the analytical procedures to be used. This includes a statement regarding the level of significance and the statistical power of the trial. It must also describe how dropouts, missing values, spurious dates and withdrawals will be handled.

Any deviation from the clinical protocol must be documented in the course of the clinical study. If applicable, modifications to the plan may be implemented by officially amending the clinical investigation plan; these amendments must be approved in writing by all involved parties. The CIP must also include detailed descriptions on how (serious) adverse events and (serious) adverse device effects will be handled, documented and classified.

Finally, the case report form (CRF) must be prepared, mirroring the clinical investigation plan, to allow a complete documentation of the study information to be recorded. CRF pages must be identifiable by version number and date and must be allocatable to the respective study subject at any time.

National status of transposition

Directive 2007/47/EC significantly amends the earlier MDD 93/42/EEC and AIMDD 90/385/EEC. It contains approximately 100 changes, some of them leading to substantial new requirements. One of the most important issues relates to the clinical evaluation and clinical investigation of medical devices in the course of the conformity assessment and during the postmarketing period. National legislative processes now take place to revise existing medical device laws. The new legislation will have to be applied by medical device manufacturers on 21 March 2010.

Dr Dieter R. Dannhorn is CEO & President and Dr Heidrun Schwabedissen is Manager Clinical Affairs at mdt medical device testing GmbH, Grenzenstrasse 13 D-88416 Ochsenhausen, Germany, tel. +49 7352 911 4 31, e-mail: dieter.dannhorn@mdt-gmbh.com, www.mdt-gmbh.com